Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFX5N3G)

• DOT Name: R-spondin-4 (RSPO4)
• Synonyms: Roof plate-specific spondin-4; hRspo4
• Gene Name: RSPO4
• Related Disease:
  Nonsyndromic congenital nail disorder 4
  Alzheimer disease
  Breast cancer
  Breast carcinoma
• UniProt ID: RSPO4_HUMAN
• Pfam ID: PF15913
• Sequence:
  MRAPLCLLLLVAHAVDMLALNRRKKQVGTGLGGNCTGCIICSEENGCSTCQQRLFLFIRR
  EGIRQYGKCLHDCPPGYFGIRGQEVNRCKKCGATCESCFSQDFCIRCKRQFYLYKGKCLP
  TCPPGTLAHQNTRECQGECELGPWGGWSPCTHNGKTCGSAWGLESRVREAGRAGHEEAAT
  CQVLSESRKCPIQRPCPGERSPGQKKGRKDRRPRKDRKLDRRLDVRPRQPGLQP
• Function: Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Regulation of FZD by ubiquitination (R-HSA-4641263)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic congenital nail disorder 4	DISTNU8N	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of R-spondin-4 (RSPO4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of R-spondin-4 (RSPO4).	[6]

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of R-spondin-4 (RSPO4).	[5]

References

• [1] Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. Am J Hum Genet. 2006 Dec;79(6):1105-9. doi: 10.1086/509789. Epub 2006 Oct 17.
• [2] Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.Alzheimers Dement. 2018 May;14(5):623-633. doi: 10.1016/j.jalz.2017.11.006. Epub 2017 Dec 20.
• [3] Clinical value of R-spondins in triple-negative and metaplastic breast cancers.Br J Cancer. 2017 Jun 6;116(12):1595-1603. doi: 10.1038/bjc.2017.131. Epub 2017 May 4.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.